Department of Medical Laboratory, Shengjing Hospital of China Medical University, 36# Sanhao Street, Heping District, Shenyang, Liaoning, 110004, China.
Graduate School of China Medical University, Liaoning, China.
Immunol Res. 2017 Oct;65(5):1059-1064. doi: 10.1007/s12026-017-8947-6.
The coexistence of immunoglobulin A nephropathy (IgAN) and idiopathic membranous nephropathy (IMN) in a few cases suggested that there could be existed a similar mechanism in pathogenesis of these two types of primary glomerulonephritis. In order to verify this hypothesis, a total of 23 reported IgAN-associated SNPs were genotyped in a cohort of 485 IMN patients and 569 healthy controls with Chinese Han origin. After Cochran-Armitage test for trend analysis, seven IgAN-associated SNPs located in the major histocompatibility complex (MHC) region were found to be significantly associated with the susceptibility of IMN, with rs9275596 as the top one (p = 1.97E-43, OR = 3.977). It was worth mentioning that the minor alleles of the SNPs conferred completely opposite effects on the pathogenesis of IMN and IgAN, suggesting quite different roles played by these SNPs for these two kinds of primary glomerulonephritis. Conditional logistic regression analysis displayed that SNPs protective from IMN (odds ratio < 1.00) were still significantly associated with IMN (p = 3.67E-4 for rs660895 and p = 1.26E-4 for rs9275224) with the most significant SNP rs9275596 as a covariate. Haplotype-based analysis showed that the seven SNPs were mapped to independent linkage disequilibrium (LD) blocks. Moreover, three out of these seven SNPs, including rs9275224, rs660895, and rs9357155, were found to be potential expression quantitative trait loci (eQTLs) for HLA-DQ molecules. Out of the purpose of identifying the causal variants for IMN within the MHC region, imputation analysis was performed using genotype data of Chinese Han released by the 1000 Genome Project and identified hundreds of SNPs potentially associated with the disease. In brief, our analysis revealed a significant association with the susceptibility of idiopathic membranous nephropathy for the IgAN-correlated SNPs. These SNPs conferred a completely different role for the pathogenesis of these two kinds of diseases.
在少数情况下，免疫球蛋白 A 肾病（IgAN）和特发性膜性肾病（IMN）共存，这表明这两种原发性肾小球肾炎的发病机制可能存在相似的机制。为了验证这一假说，我们对来自中国汉族的 485 例 IMN 患者和 569 例健康对照者的队列进行了 23 项已报道的 IgAN 相关单核苷酸多态性（SNP）的基因分型。在 Cochran-Armitage 趋势分析后，发现位于主要组织相容性复合体（MHC）区域的 7 个 IgAN 相关 SNP 与 IMN 的易感性显著相关，其中 rs9275596 为最显著的 SNP（p = 1.97E-43，OR = 3.977）。值得注意的是，SNP 的次要等位基因对 IMN 的发病机制有完全相反的影响，这表明这些 SNP 对这两种原发性肾小球肾炎的作用截然不同。条件逻辑回归分析显示，IMN 的保护 SNP（比值比 < 1.00）与 IMN 仍显著相关（rs660895 的 p = 3.67E-4，rs9275224 的 p = 1.26E-4），最显著的 SNP rs9275596 作为协变量。基于单体型的分析表明，这 7 个 SNP 映射到独立的连锁不平衡（LD）块。此外，这 7 个 SNP 中有 3 个（包括 rs9275224、rs660895 和 rs9357155）被发现是 HLA-DQ 分子的潜在表达数量性状基因座（eQTLs）。为了确定 MHC 区域内与 IMN 相关的因果变异，我们使用 1000 基因组计划发布的中国汉族基因型数据进行了推测分析，并鉴定了数百个可能与该疾病相关的 SNP。总之，我们的分析揭示了 IgAN 相关 SNP 与特发性膜性肾病易感性的显著关联。这些 SNP 对这两种疾病的发病机制有完全不同的作用。
